Mechanism of amido-thiourea catalyzed enantioselective imine hydrocyanation: Transition state stabilization via multiple non-covalent interactions

Published on Web 09/24/2009

Mechanism of Amido-Thiourea Catalyzed Enantioselective

Imine Hydrocyanation: Transition State Stabilization via

Multiple Non-Covalent Interactions

Stephan J. Zuend and Eric N. Jacobsen*

HarVard UniVersity, Department of Chemistry & Chemical Biology, Cambridge, Massachusetts 02138

Received July 15, 2009; E-mail: jacobsen@chemistry.harvard.edu

Abstract: An experimental and computational investigation of amido-thiourea promoted imine hydrocya-

nation has revealed a new and unexpected mechanism of catalysis. Rather than direct activation of the

imine by the thiourea, as had been proposed previously in related systems, the data are consistent with a

mechanism involving catalyst-promoted proton transfer from hydrogen isocyanide to imine to generate

diastereomeric iminium/cyanide ion pairs that are bound to catalyst through multiple noncovalent interactions;

these ion pairs collapse to form the enantiomeric R-aminonitrile products. This mechanistic proposal is

supported by the observation of a statistically signiﬁcant correlation between experimental and calculated

enantioselectivities induced by eight different catalysts (P , 0.01). The computed models reveal a basis

for enantioselectivity that involves multiple stabilizing and destabilizing interactions between substrate and

catalyst, including thiourea-cyanide and amide-iminium interactions.

Introduction

interactions needed to disfavor competing pathways. If that is

the case, then the penalty of avoiding repulsive steric interactions

Catalysis by neutral, organic, small molecules capable of

binding and activating substrates solely via noncovalent

interactionssparticularly H-bondingshas emerged as an im-

portant approach to enantioselective synthesis over the past

decade.¹The mechanisms by which such small-molecule

catalysts induce high enantioselectivity may be quite different

from those employed by catalysts that rely on covalent interac-

tions with substrates. The latterstypiﬁed by chiral Lewis acids,²

transition metal complexes,³and secondary amine deriv-

atives⁴sare generally understood to induce enantioselectivity

through steric destabilization of all but the dominant pathway.

Repulsive steric effects are strongly distance dependent⁵and

expected to be most pronounced in covalently bound intermedi-

ates and transition states. Attractive noncovalent interactions

are weaker, less distance dependent, less directional, and more

affected by entropy than covalent interactions.⁶This analysis

deﬁnes the challenge for achieving high enantioselectivity

through noncovalent interactions alone: the attractive nonco-

valent interaction (e.g., H-bonding) that binds the enantiose-

lectivity-determining transition structure to the catalyst may be

substantially less distance dependent than the repulsive steric

by structural reorganization should be relatively small. However,

the conformational constraint required for high stereoinduction

may be achieved, in principle, if multiple noncovalent attractive

interactions are operating in concert. Enzymes engage such

cooperative effects as a general principle,^7,8and we are

interested in exploring the extent to which the interplay of weak,

noncovalent interactions is also important in highly selective

reactions promoted by small molecule catalysts.⁹

The urea- and thiourea-catalyzed enantioselective hydrocya-

nation of imines are important examples of small-molecule

catalyzed reactions thought to involve only noncovalent substrate-

catalyst interactions (Scheme 1).¹⁰In 2002, a preliminary

mechanistic analysis of this reactionsbased on NMR spectro-

copic, kinetic, structure-activity, and theoretical studiessrevealed

that the urea functionality of 1b is responsible for catalytic

(6) For a tabulation of the orientation- and distance-dependence of

attractive non-covalent interactions, see: ref 5, p 28. For example,

the strength of a charge-dipole interactionswhich approximates the

electrostatic component of a hydrogen bondsis proportional to cos

θ/r². If the energy of this interaction is 5 kcal/mol when bond length

and orientation are optimal, then either a 25% increase in bond length

or a 45° rotation of the dipole will cost less than 2 kcal/mol.

(7) For a discussion of and leading references to models for enantiose-

lectivity in biological systems, see: Sundaresan, V.; Abrol, R. Protein

Sci. 2002, 11, 1330–1339.

(1) Review, historical perspective, and leading references: Doyle, A. G.;

Jacobsen, E. N. Chem. ReV. 2007, 107, 5713–5743.

(2) For classic examples, see: Johnson, J. S.; Evans, D. A. Acc. Chem.

Res. 2000, 33, 325–335.

(8) For leading references to cooperative mechanisms in enzymatic and

small-molecule catalysis, see ref 16c.

(9) For a recent discussion of additive effects in supramolecular

chemistry, see: Schneider, H.-J. Angew. Chem., Int. Ed. 2009, 48,

3924–3977.

(3) Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006,

39, 747–760.

(4) Recent reviews: (a) Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta

2006, 39, 79–87. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List,

B. Chem. ReV. 2007, 107, 5471–5569.

(10) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120,

4901–4902. For subsequent studies, see: (b) Sigman, M. S.; Vachal,

P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279–1281.

(c) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867–870. (d) Su,

J. T.; Vachal, P.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343, 197–

200.

(5) For a detailed discussion, see: Israelachvili, J. Intermolecular &

Surface Forces, 2nd ed.; Academic Press: London, 1991; pp 109-

121. The strength of repulsive non-bonding interactions is roughly

proportional to (1/r)¹². Within this model, a 25% increase in r leads

to a 93% decrease in interaction energy.

9

15358 J. AM. CHEM. SOC. 2009, 131, 15358–15374

10.1021/ja9058958 CCC: $40.75  2009 American Chemical Society

Amido-Thiourea Catalyzed Imine Hydrocyanation

A R T I C L E S

Scheme 1. Enantioselective Imine Hydrocyanation Catalyzed by

Chiral (Thio)urea Derivatives

Figure 1. Dual H-bonding interaction between imine and thiourea. The

three-dimensional structure is a local minimum at the B3LYP/6-31G(d,p)

level of theory.

Scheme 2. Examples of Proposed Anion-Binding Mechanisms

Promoted by Chiral (Thio)urea Derivatives Involving (A) N-acyl

iminium/chloride and (B) Oxocarbenium/chloride Ion Pairs

activity and that the imine substrate engages in a ground-state

interaction with the catalyst via a dual H-bonding interaction

to the urea protons (Figure 1).¹¹This study helped to establish

that simple H-bond donors could serve as useful chiral small-

molecule catalysts and laid the foundation for much of the

subsequent work in this ﬁeld.¹However, the mechanism of

catalysis, and speciﬁcally the question of whether the H-bonding

interaction between imine and (thio)urea persisted in the rate-

or enantioselectivity-determining transition state, could not be

elucidated on the basis of this study.

It was discovered subsequently that urea and thiourea

derivatives engage a variety of weakly basic electrophiles,

including N-acyl iminium/chloride¹²and oxocarbenium/chloride

ion pairs,¹³in catalytic asymmetric reactions. On the basis of

substituent and solvent effects, as well as the well-known anion-

binding properties of ureas and thioureas,¹⁴this work led to

the proposal that catalysis occurs by abstraction of an anionic

leaving group (e.g., Cl^-) (Scheme 2).^12b,15

The notion that multiple mechanistic channels are available

to (thio)urea derivatives in catalysis of nucleophile-electrophile

addition reactionssand speciﬁcally that H-bonding may occur

either directly to the electrophile or to an anionic counterion or

nucleophile in the enantioselectivity-determining transition

structureshas emerged from theoretical studies of reactions

promoted by tertiary amino-thiourea derivatives.¹⁶For example,

in the thiourea-catalyzed cyanosilylation of ketones, relatively

small differences in activation energy were calculated between

mechanisms involving thiourea-ketone and thiourea-cyanide

interactions (Scheme 3).^16cAnalogous considerations may apply

to imine hydrocyanation reactions, raising the possibility that

the thiourea-imine interactions identiﬁed in the preliminary

mechanistic work might lie off the productive catalytic cycle.

The mechanism of imine hydrocyanation has been subjected

to rigorous scrutiny in the context of nonasymmetric methods,

whereas current understanding of enantioselective catalytic

variants is more qualitative. Hydrocyanation of imines is

promoted by polar, protic solvents such as methanol, but

proceeds slowly in nonpolar or aprotic solvents, and is inhibited

under basic conditions.^17,18Insight into the timing and precise

mechanism of the σ-bond formation and protonation steps is

available from classical studies of nucleophilic additions to

carbonyl and imine electrophiles conducted on reactions run in

aqueous or alcoholic media.^19,20Under these conditions, solvent

molecules can assist in proton transfer steps that may be required

for reaction.²¹Indeed, experimental and theoretical studies of

nonasymmetric imine hydrocyanation have led to the proposal

that solvent molecules (e.g., water or methanol) participate in

charge separation and promote proton transfer from HCN to

the imine, resulting in the formation of a highly reactive

iminium/cyanide ion pair that collapses to afford the R-amino-

nitrile product (e.g., Scheme 4A).^22,23In contrast, asymmetric

catalysis of imine hydrocyanation by chiral Lewis or Brønsted

acids is generally most effective in nonpolar, aprotic solvents,

(17) (a) Ogata, Y.; Kawasaki, A. J. Chem. Soc., B 1971, 325–329. See

also: (b) Taillades, J.; Commeyras, A. Tetrahedron 1974, 30, 127–

132. (c) Taillades, J.; Commeyras, A. Tetrahedron 1974, 30, 2493–

2501.

(11) (a) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012–

10014. See also: (b) Vachal, P. Ph.D. Thesis, Harvard University,

Cambridge, MA, March, 2003.

(12) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,

10558–10559. (b) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;

Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404–13405.

(13) Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.

2008, 130, 7198–7199.

(18) In contrast, cyanation of carbonyl compounds is subject to basic

catalysis: Ching, W.-M.; Kallen, R. G. J. Am. Chem. Soc. 1978, 100,

6119–6124, and refs therein.

(19) Jencks, W. P. Chem. ReV. 1972, 72, 705–718.

(20) Jencks, W. P. Catalysis in Chemistry and Enzymology; Dover

Publications: New York, 1987.

(14) For a survey of the anion binding properties of ureas and thioureas,

see: Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor Chemistry;

RSC Publishing: Cambridge, 2006; pp 193-205.

(15) For a review and an analysis of the anion-binding properties of urea

derivatives in the context of catalysis, see: Zhang, Z. G.; Schreiner,

P. R. Chem. Soc. ReV. 2009, 38, 1187–1198. This paper also contains

an up-to-date list of reviews in this area.

(16) (a) Hamza, A.; Schubert, G.; Soo´s, T.; Pa´pai, I. J. Am. Chem. Soc.

2006, 128, 13151–13160. (b) Hammar, P.; Marcelli, T.; Hiemstra,

H.; Himo, F. AdV. Synth. Catal. 2007, 349, 2537–2548. (c) Zuend,

S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 15872–15883.

(21) Guthrie, J. P. J. Am. Chem. Soc. 1996, 118, 12886–12890, and refs

therein.

(22) Arnaud, A.; Adamo, C.; Cossi, M.; Milet, A.; Valle´e, Y.; Barone,

V. J. Am. Chem. Soc. 2000, 122, 324–330.

(23) In early studies, it was also proposed that solvent was involved in a

proton relay step (i.e., the source of the proton on the R-aminonitrile

product is solvent rather than HCN). However, no role for proton

relay by water could be identiﬁed in ref 22, and water was proposed

to promote hydrocyanation through the formation of multiple

hydrogen bridges.

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J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009 15359

A R T I C L E S

Zuend and Jacobsen

Scheme 3. Competing Enantioselectivity-Determining Pathways in the Amino-Thiourea Catalyzed Cyanosilylation of Ketones (ref 16c)^a

^aMechanism A is favored, but both pathways are energetically accessible.

Scheme 4. Proposed Transition Structures for (A) Water-Mediated^aand (B) Chiral Lewis-Acid Catalyzed^bImine Hydrocyanation

^aReference 22. ^bReference 25b.

such as toluene.²⁴Solvent-mediated proton transfer is not

possible under these conditions, and most mechanistic proposals

for asymmetric imine hydrocyanation invoke direct interactions

between imine and Lewis or Brønsted acid (e.g., Scheme 4B),²⁵

rather than formation of an iminium/cyanide ion pair. In these

cases, protonation is proposed to occur after nucleophilic

addition,^25a,bor by the catalyst itself.^25c-eThe mechanisms

proposed until now for nonasymmetric and asymmetric imine

hydrocyanation are therefore fundamentally different,²⁶and bear

close parallels to the two limiting mechanisms outlined in

Scheme 3 for thiourea catalysis of ketone cyanosilylation.

In this paper, we describe a detailed experimental and

computational study of highly enantioselective imine hydro-

cyanation reactions catalyzed by recently discovered urea and

thiourea derivatives. We have found that the mechanism of

thiourea-catalyzed imine hydrocyanation does not involve

productive thiourea-imine interactions (Figure 1); instead, all

data are consistent with a mechanism in which imine protonation

by hydrogen cyanide precedes nucleophilic addition (e.g., as in

the water-mediated reaction, Scheme 4A). This study has

identiﬁed a role for each functional group on the chiral catalyst,

and has revealed a basis for catalysis and enantioinduction that

involves multiple stabilizing electrostatic interactions between

catalyst and the bound iminium and cyanide ions.

Results and Discussion

A. Identiﬁcation of a Simpliﬁed Hydrocyanation Catalyst.

Our efforts to carry out detailed investigations of imine

hydrocyanation reactions catalyzed by thiourea Schiff base

catalysts such as 1a-c were limited severely by the structural

complexity of the catalysts. However, we discovered recently

that N-benzhydryl imines (2) undergo highly enantioselective

imine hydrocyanation with the much simpler amido-thiourea

catalyst 4a (Table 1).²⁷This reaction displays broad substrate

scope, with aldimines bearing either sp³- or sp²-hybridized

substituents undergoing hydrocyanation in high yield and

enantioselectivity (entries 1-7). Urea-analogue 4b promotes

hydrocyanation to afford R-aminonitriles in similar enantiomeric

excess and yield as thiourea 4a (entries 8-10). This observation

indicates that these catalysts operate by similar mechanisms as

H-bond donors and that the nucleophilicity at sulfur of the

thiourea catalyst 4a does not play a direct role in the catalytic

mechanism.

(24) Recent reviews and leading references: (a) Gro¨ger, H. Chem. ReV.

2003, 103, 2795–2827. (b) Na´jera, C.; Sansano, J. M. Chem. ReV.

2007, 107, 4584–4671. (c) Connon, S. J. Angew. Chem., Int. Ed.

2008, 47, 1176–1178.

(25) (a) Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki,

M. Angew. Chem., Int. Ed. 2000, 39, 1650–1652. (b) Josephsohn,

N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.

Soc. 2001, 123, 11594–11599. (c) Li, J.; Jiang, W.-Y.; Han, K. L.;

He, G.-Z.; Li, C. J. Org. Chem. 2003, 68, 8786–8789. (d) Rueping,

M.; Sugiono, E.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, 2617–

2619. (e) Simo´n, L.; Goodman, J. M. J. Am. Chem. Soc. 2009, 131,

4070–4077.

(26) For a recently reported exception to this generalization, see: Negru,

M.; Schollmeyer, D.; Kunz, H. Angew. Chem., Int. Ed. 2007, 46,

9339–9341.

(27) Zuend, S. J.; Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E. N. Nature,

Accepted for publication.

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15360 J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009

Amido-Thiourea Catalyzed Imine Hydrocyanation

A R T I C L E S

Table 1. Asymmetric Imine Hydrocyanation Using Catalysts 4a

and 4b

entry

cat.

imine 2 (R ))

cat. (mol %)

yield^a(%)

ee^b(%)

1

2

3

4

5

6

7

8

9

4a

4b

tert-butyl (a)

p-OMeC₆H₄(b)

p-MeC₆H₄(c)

C₆H₅(d)

p-ClC₆H₄(e)

p-CF₃C₆H₄(f)

p-CNC₆H₄(g)

p-OMeC₆H₄(b)

C₆H₅(d)

2

10

2

99

98

97

98^c

96^c

98

97

96^c

93

99

98

96

93

96

93

92

Figure 2. Rate dependence on [HCN] and [imine]. Plot of rate of imine

hydrocyanation catalyzed by 4a ([cat]_tot) 0.0040 M) versus [imine] at

different [HCN]_i. Each set of points represents the average rate determined

from two individual kinetics experiments with [imine]_i) 0.20 M (red points)

or [imine]_i) 0.10 M (blue points). The black curves represent least-squares

ﬁts of the experimental rate versus conversion data to eq 1.

10

p-CF₃C₆H₄(f)

^aIsolated yields of 3 after silica gel chromatography of reactions run

on 1.0 mmol scale. ^bEnantiomeric excess of puriﬁed samples

determined by chiral HPLC analysis using commercially available

columns. ^cReaction run at 0 °C.

B. Kinetic Studies of (Thio)urea-Catalyzed Imine Hydrocya-

nation. To establish the stoichiometry of the rate-limiting

transition structure, we carried out a detailed kinetic analysis

of the imine hydrocyanation reaction catalyzed by 4a. Rate

studies were executed using representative substrate 2a at

synthetically relevant concentrations using in situ infrared

spectroscopy. The kinetic experiments were executed under

homogeneous conditions, in which HCN was generated in situ

by addition of controlled amounts of MeOH to solutions of

TMSCN in toluene.²⁸Data obtained from eighteen independent

experiments over a range of concentrations of HCN (0.06-0.35

M), 2a (0.01-0.15 M), and catalyst 4a (0.00080-0.0064 M)

were used to derive an empirical rate law for the reaction.

Kinetic modeling of the experimental data reveals good agree-

ment with the rate law given by eq 1 (Figures 2 and 3):^29-31

Figure 3. Rate dependence on [cat]_totand [imine]. Plot of rate of imine

hydrocyanation ([HCN]_i) 0.25 M) catalyzed by 4a versus [imine] at

different [cat]_tot. Each set of points represents the average rate determined

from two individual kinetics experiments with [imine]_i) 0.20 M. The black

curves represent least-squares ﬁts of the experimental rate versus concentra-

tion data to eq 1.

The deviation from ﬁrst-order kinetics might be explained by

irreversible catalyst deactivation. “Same excess” experiments³²

were carried out to establish whether consistent kinetic behavior

(i.e., the same rate law) was maintained throughout the course

of the entire reaction. The perfect overlap of kinetic runs

executed at different ratios but same excess of [HCN] relative

to [imine] (compare red and blue points in Figure 2) reveals

that no signiﬁcant catalyst deactivation occurs, and that product

rate ) k[HCN]^a[imine]^b[cat]^c_tot

k ) 0.58 ( 0.02 M^-2s^-1, a ) 1.09 ( 0.02, b )

1.06 ( 0.01, c ) 0.812 ( 0.007 (1)

The values of the exponents a and b are both approximately

1, and thus analysis of the data reveals an approximately ﬁrst-

order dependence of rate on both [HCN] and [imine]. In contrast,

the value of c is somewhat less than 1, and the deviation from

unity in the rate dependence on [cat]_totappears to be statistically

signiﬁcant.

(31) The kinetic modeling was executed using methods described previ-

ously (ref 16c, and refs therein): experimental IR data in the form

absorbance Versus time were ﬁrst converted to the form concentration

Versus time by application of Beer’s Law. These data were converted

to the form rate Versus concentration by least-squares ﬁtting of the

concentration Versus time data to a 7th-order polynomial followed

by analytical differentiation of the polynomial. For this approach to

be effective, a high data collection rate is necessary, and IR spectra

were collected every 15 s for the entire course of the reaction. This

approach also requires that the reaction mixture solution be com-

pletely homogeneous, and thus IR data collected in the ﬁrst few

minutes after addition of the last reagent are intrinsically inaccurate.

In the fastest reactions, there is insufﬁcient data at low %-conversion

to apply this approach (i.e., there are too few IR spectra collected

within approximately the ﬁrst 25% conversion to allow for accurate

curve ﬁtting). For consistency, all kinetic analyses used data from

25-95% conversion of imine (i.e., [imine] ) 0.01-0.15 M where

[imine]_i) 0.20 M).

We considered different possible explanations for the devia-

tion from a strict ﬁrst-order dependence of rate on [cat]_tot. (a)

(28) Conversion of TMSCN to HCN could be monitored directly by in

situ IR spectroscopy, or indirectly by ¹H-NMR spectroscopy

in C₆D_6.Conversion of 2a was determined by monitoring the height

of the CdN stretch at 1670 cm^-1relative to a two-point baseline

(1570-1770 cm^-1).

(29) Non-linear least-squares ﬁtting and statistical analysis was executed

using SigmaPlot 10.0 purchased from Systat Software.

(30) R²) 0.9955 for the ﬁt of the data to eq 1. Details and kinetic data

in tabular format are included in the Supporting Information.

(32) Blackmond, D. G. Angew. Chem., Int. Ed. 2005, 44, 4302–4320.

9

J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009 15361

A R T I C L E S

Zuend and Jacobsen

Scheme 5. Limiting Mechanisms for Imine Hydrocyanation

Proceeding through (A) an Iminium Ion or (B) an R-Amidonitrile

Anion

inhibition is insigniﬁcant.³³(b) In principle, the deviation from

ﬁrst-order kinetics might also be explained by competitive

uncatalyzed imine hydrocyanation under the reaction conditions.

However, the initial rate of the uncatalyzed reaction is ap-

proximately 5% of the initial rate of the reaction using the lowest

catalyst concentration (0.00080 M). In addition, the enantiomeric

ratio is independent of [cat]_totunder the conditions used in the

kinetic analysis (13:1-14:1 er). Both observations indicate that

uncatalyzed background reaction is negligible under the condi-

tions of the kinetic analysis. (c) Having ruled out other possible

explanations for this effect, we ascribe the small deviation from

a ﬁrst-order rate dependence on [cat]_totreversible formation of

an inactive catalyst dimer at high [cat]_tot.^34,35However, it is

important to note that this effect is small and that the precise

origins of this effect do not appear to have any bearing on the

mechanism of catalysis or enantioinduction, as the enantiomeric

excess of the product is the same at different catalyst concentra-

tion (vide supra).

Figure 4. Rate dependence of imine hydrocyanation catalyzed by 4a or

4b on substrate electronic properties. Plot of the logarithm of pseudoﬁrst-

order rate constant (log(k_obsd)) versus σ_pfor the hydrocyanation of

p-substituted imines 2b-2g ([2]_i) 0.040 M) by TMSCN/MeOH (0.50 M)

mediated by thiourea catalyst 4a ([cat]_tot) 0.0020 M, b) or urea catalyst

4b ([cat]_tot) 0.0020 M, 2) versus σ_p. The black curves represent least-

squares ﬁts to f(x) ) a + F x, a_thiourea) -2.74 ( 0.06, F_thiourea) -2.7 (

0.2; a_urea) -3.25 ( 0.08, F_urea) -2.5 ( 0.2.

the R-aminonitrile product (Scheme 5B). To evaluate the rela-

tive timing of the protonation and cyanide addition steps in the

thiourea-catalyzed imine hydrocyanation reaction, we sought

to assess the sense and degree of charge development at the

imine-derived nitrogen in the rate-determining transition state.

The ﬁrst-order dependence on both [imine] and [HCN] observed

experimentally indicates that the imine reactant is not associated

with HCN or catalyst in the resting state. Thus a mechanism

that involves rate-limiting formation of an iminium ion inter-

mediate (e.g., step 1 in Scheme 5A) will be characterized by

an increase in positive charge at nitrogen and faster rates are

expected with substrates that better stabilize that positive charge.

In contrast, a mechanism that involves an R-amidonitrile

intermediate is expected to be characterized by faster rates with

substrates that better stabilize negative charge. To distinguish

between these possibilities, we measured the rates of hydro-

cyanation of substituted benzaldehyde-derived imines promoted

by thiourea catalyst 4a and urea analogue 4b (Figure 4).³⁸

Hammett plots reveal negative F-values that are similar in

The kinetic data do not distinguish between the two funda-

mentally different mechanisms in Scheme 5: (a) protonation of

the imine to form a transient iminium ion, followed by

nucleophilic addition of cyanide anion to form the R-aminonitrile

product (Scheme 5A);^36,37or (b) addition of cyanide to an imine

to form an R-amidonitrile anion, followed by protonation to form

(33) We have only carried out “same excess” experiments at one [cat]_tot,

and it is possible that at other [cat]_tot, some irreversible catalyst

deactivation occurs.

(34) A ﬁt to a kinetic model that allows for reversible catalyst dimer

formation provides an excellent agreement with the experimental data:

rate ) k [HCN] [imine](2 [cat]_tot)/(1 + ꢀj(1 + 8K_dim[cat]_tot), k )

1.74 ( 0.04 M^-2s^-1, K_dim) 55 ( 6 M^-1, R2 ) 0.9932. A derivation

of this rate law and the corresponding ﬁgures are included in the

Supporting Information. A ﬁt to rate ) k [HCN][imine][cat]_tot

provides comparatively poor agreement with the experimental data

(see Supporting Information).

(38) Reactions were monitored by sequential removal of aliquots and

subsequent 1H-NMR spectroscopic analysis versus 1,3,5-trimethoxy-

benzene internal standard. Pseudo ﬁrst-order rate constants (k_obsd) were

_obsdx

obtained by a non-linear least squares ﬁt to f(x) ) a e^-k. Details

and kinetic data in tabular format are provided in the Supporting

Information.

(35) Aggregation of thiourea catalysts is precedented: (a) ref 16c. (b)

Ta´rka´nyi, G.; Kira´ly, P.; Varga, S.; Vakulya, B.; Soo´s, T. Chem.sEur.

J. 2008, 14, 6078–6086. (c) Oh, S. H.; Rho, H. S.; Lee, J. W.; Lee,

J. E.; Youk, S. H.; Chin, J.; Song, C. E. Angew. Chem., Int. Ed.

2008, 41, 7872–7875.

(39) σ_pvalues were obtained from Hansch, C.; Leo, A.; Taft, R. W. Chem.

ReV. 1991, 91, 165–195.

(40) A similar F value was obtained from a series of competition

experiments in imine hydrocyanation reactions catalyzed by 1b

(Vachal, P. Unpublished results). To our knowledge, no other

Hammett studies of catalytic asymmetric imine hydrocyanation

reactions have been reported; it is thus not possible to establish

whether this observation is general.

(36) Methanol-mediated racemic imine hydrocyanation proceeds via a

mechanism that involves buildup of positive charge on the imine (F

)-1.1): ref 17a.

(37) A concerted [3 + 2] cycloaddition mechanism is also consistent with

the kinetic data, and represents an intermediate case. Gas-phase

transition structures for a concerted, asynchronous [3 + 2] cycload-

dition between an imine and HNC have been located using both DFT

and ab initio methods. This process has a calculated activation barrier

of 43 kcal/mol. Inclusion of bulk water reduces the calculated

activation free energy of the concerted process to 19 kcal/mol.

Whereas the gas phase transition structure visually approximates the

aqueous transition structure, the latter is characterized by longer

breaking N-H and forming C-C bonds, and is more accurately

described as an iminium/cyanide ion pair. Explicit inclusion of two

water molecules decreases the activation free energy to 16 kcal/mol,

and results in a non-concerted, multi-step iminium/cyanide ion pair

mechanism: ref 22.

(41) The observed negative F values are large compared with those

observed in other reactions of imines. In reactions that involve imine

protonation followed by nucleophilic addition (e.g., in imine hy-

drolysis under non-acidic conditions), the negative Hammett cor-

relation of imine basicity approximately cancels the positive Hammett

correlation of iminium ion electrophilicity. Large negative Hammett

correlations have been observed for additions for the acid-catalyzed

addition of amine nucleophiles to oximes. For a series of classic

studies examining substituent effects on imine basicity, see: (a)

Cordes, E. H.; Jencks, W. P. J. Am. Chem. Soc. 1963, 85, 2843–

2848. (b) Koehler, K.; Sandstrom, W.; Cordes, E. H. J. Am. Chem.

Soc. 1964, 86, 2413–2419. (c) Archila, J.; Bull, H.; Lagenaur, C.;

Cordes, E. H. J. Org. Chem. 1971, 36, 1345–1347.

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15362 J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009

Amido-Thiourea Catalyzed Imine Hydrocyanation

A R T I C L E S

catalyzed by chiral catalysts 4a and 4b. The derived F value of

-3.3 ( 0.1 is slightly larger than in the enantioselective

reactions, indicating that imine hydrocyanation catalyzed by 5

involves a somewhat greater degree of positive charge buildup

than imine hydrocyanation catalyzed by 4a or 4b. Nonetheless,

because the kinetic behavior and F values in imine hydrocya-

nation reactions catalyzed by 4a and 5 are similar, it appears

reasonable to conclude that these catalysts promote hydrocya-

nation by analogous mechanisms.⁴⁷

Figure 5. Rate dependence of imine hydrocyanation on substrate electronic

properties. Logarithm of pseudoﬁrst order rate constant (log(k_obsd)) versus

σ_pof the hydrocyanation of p-substituted imines 2b-2f ([2]_i) 0.040 M)

mediated by TMSCN/MeOH (0.50 M) and thiourea catalyst 5 (0.0050 M).

The black curve depicts an unweighted least-squares ﬁt to f(x) ) a + F x

(F ) -3.3 ( 0.1). The experiments leading to Figures 4 and 5 were executed

under identical conditions, except that the concentration of 5 was 2.5-fold

greater than of 4a or 4b.

C. Correlation between Catalyst Structural Properties and

Reaction Rate and Enantioselectivity. The rate of imine hydro-

cyanation is only slightly lower with Schreiner’s catalyst (5)

than with the chiral amidothiourea 4a (compare Figures 4 and

5, or data in the Supporting Information), indicating that an

H-bond donor alone is sufﬁcient for efﬁcient catalysis of this

reaction.⁴⁸To glean insight into the mechanism of stereoinduc-

tion in the asymmetric reaction, the impact of catalyst structural

properties on the rate and enantioselectivity of hydrocyanation

of imine 2a was assessed by a combination of kinetic analysis

using in situ IR spectroscopy and ee determinations using chiral

HPLC analysis.⁴⁹Analysis of the data indicates that replacing

the 3,5-bis-triﬂuoromethylanilino group with less electron-

deﬁcient anilines leads to a substantial decrease in activity

without substantial change in enantioselectivity (Table 2, entries

1-3). Urea-derived catalyst 4b is slightly less active and

enantioselective than 4a (entries 1 and 4). In contrast, altering

the properties of the amino acid-derived portion of the catalyst

leads to substantial decreases in both activity and enantiose-

lectivity (entries 1, 5-10). The (R)-enantiomer is the major

product in reactions promoted by (S)-amino acid-derived

catalysts in all but one case (entry 8).⁵⁰The observation that

catalyst 4a is both the most enantioselective and the most

reactive catalyst identiﬁed in this series raises the possibility

that the stereochemical outcome of the reaction is a result of

not only selective destabilization of the transition state leading

magnitude (F_thiourea) -2.7 ( 0.2; F_urea) -2.5 ( 0.2),³⁹

consistent with substantial positive charge buildup in the

transition state compared with the imine reactant.^40-42These

data provide compelling evidence against the involvement of

an R-amidonitrile anion (Scheme 5B) in the (thio)urea-catalyzed

imine hydrocyanation, and point instead to an iminium ion

mechanism (Scheme 5A).^43,44

Schreiner’s achiral thiourea (5)⁴⁵is also an efﬁcient catalyst

for hydrocyanation of imine 2a. Kinetic analysis under condi-

tions similar to those used with chiral catalyst 4a affords an

adequate ﬁt to eq 2:⁴⁶

rate ) k[HCN][imine][cat]_totk ) 1.205 ( 0.008 M^-2s^-1

(2)

A Hammett study of the hydrocyanation catalyzed by 5

reveals that electron-rich substrates react more rapidly than

electron-poor ones (Figure 5), as is the case for reactions

(42) The observed negative F-values are small compared with those of

reactions that proceed through a cationic transition structure not

stabilized by a heteroatom; e.g., acid-catalyzed hydration of styrene

derivatives: Schubert, W. M.; Keeffe, J. R. J. Am. Chem. Soc. 1972,

94, 559–566.

(47) Achiral thiourea 5 catalyzes hydroalkoxylation of electron-rich oleﬁns.

The proposed mechanism for this transformation involves oleﬁn

protonation followed by alkoxide addition in a formally concerted

but highly asynchronous manner: Kotke, M.; Schreiner, P. R.

Synthesis 2007, 779–790. This proposal is analogous to the proposed

mechanism of 4a-catalyzed imine hydrocyanation (vide infra).

(48) Larger differences in rate between reactions promoted by 4a and 5

are observed with more electron-deﬁcient substrates (Figures 4 and

5). (The experiments that led to Figures 4 and 5 are run under

identical conditions, except that the concentration of 5 is 2.5-fold

greater than that of 4a.).

(49) Relative rate data were obtained under pseudo ﬁrst-order conditions

at 0 °C. Because enantioselectivity depends on the reaction conditions,

intrinsic enantiomeric ratios (er) were estimated from experiments

run at high dilution ([imine]_i) 0.020 M,-30 °C). Details are included

in the Supporting Information.

(50) The relative rate data should be interpreted with caution, as relative

rates do not necessarily correlate with the ability of catalysts to

stabilize the rate-limiting hydrocyanation transition structures; dif-

ferences in catalyst aggregation, internal bond rotation, and potential

to catalyze hydrocyanation via higher-order mechanisms could each

contribute to the relative rate constants. For a discussion on the

limitations of using “k_rel” for the elucidation of complex reaction

mechanisms, see: Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2000,

122, 2452–2458.

(43) The gas phase basicity (proton afﬁnity) of para-substituted benzal-

dehyde-derived imines N-H imines was also computed by DFT

methods (B3LYP/6-31G(d)). Details are provided in the Supporting

Information.

(44) A mechanism that involves positive charge buildup on the organic

electrophile would likely also involve negative charge buildup on

the nucleophile; thus such a mechanism is expected to be character-

ized by high reaction rates with nucleophiles that are able to stabilize

negative charge. The structural simplicity of cyanide anion that

renders it ideal for computational analysis (vide infra) does not allow

a direct test of this hypothesis. However, thiourea-catalyzed asym-

metric imine hydrophosphonylation appears to be mechanistically

related to imine hydrocyanation, and proceeds most rapidly with

electron-deﬁcient phosphites: Joly, G. D.; Jacobsen, E. N. J. Am.

Chem. Soc. 2004, 126, 4102–4103. The observation that aprotic

phosphites are unreactive foreshadows the conclusion that proton

transfer from nucleophile precursor to imine precedes nucleophilic

addition (vide infra).

(45) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217–220.

(46) Data are included in the Supporting Information. The ﬁt to eq 2

affords R₂) 0.980. A ﬁt to rate ) k[HCN]^a[imine]^b[cat]_t^c_otaffords:

k_cat) 2.8 ( 0.3 M^-2s^-1, a ) 1.03 ( 0.04, b ) 0.97 ( 0.02, c )

1.17 ( 0.02, R₂) 0.987.

9

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A R T I C L E S

Zuend and Jacobsen

Table 2. Correlation between Catalyst Structural Properties and Reaction Rate and Enantioselectivity in the Hydrocyanation of 2a

^aDetermined by in situ IR spectroscopy under pseudoﬁrst order conditions: [imine]_i) 0.06 M, [TMSCN]_tot) 0.80 M, [MeOH] ) 0.60 M, [cat]_tot

)

0.006 M, toluene, 0 °C. Rate constants were determined by a ﬁt to f(x) ) y_o+ a e^k^obsd^x, where x ) absorbance. ^bDetermined by chiral HPLC analysis of

isolated samples. Average of two independent experiments (1 standard deviation. Conditions: -30 °C, 2 equiv TMSCN/MeOH, toluene (0.02 M),

c

14-20 h. Estimated with ∆∆G^q) -RT ln([R]/[S]), T ) 243.15.

to the minor (S)-enantiomer, but also of selective stabilization

of the transition state leading to the major (R)-enantiomer.

D. Consideration of Limiting Mechanisms for Thiourea-

Catalyzed Imine Hydrocyanation: Computational Studies with a

Simpliﬁed Model System. The kinetic and mechanistic analyses

described above indicate that thiourea-catalyzed imine hydro-

cyanation is accompanied by positive-charge buildup on the

imine, and likely involves the intermediacy of an iminium ion.

The structure-activity-enantioselectivity relationship data pro-

vide qualitative information about the critical features of the

catalyst, revealing for example that the structures of both the

amide and the amino-acid derived portion of the catalyst are

critical for both enantioselectivity and activity. In principle,

further information about substrate-catalyst interactions might

be obtained from spectroscopic or crystallographic analyses of

substrate-catalyst complexes. However, such complexes are

expected to be weakly bound, and the rates of formation and

dissociation of such complexes will almost certainly be much

greater than the rate of the catalytic reaction.⁵¹Under these

conditions, spectroscopic analyses are unlikely to provide insight

into interactions that occur in transition states.^52,53

In contrast, computational chemistry is well-suited to the

characterization of complex transition states in organic chemical

reactions,⁵⁴including in the context of asymmetric organoca-

(51) For an example in the context of organocatalysis in which the free

energy and enthalpy of substrate binding to an H-bond donor has

been determined, see: ref 45.

(52) For a review of the Curtin-Hammett principle, see: Seeman, J. I.

Chem. ReV. 1983, 83, 83–134.

(53) For a well-studied example of a small molecule-catalyzed reaction

in which the rate of substrate-catalyst complex formation and

dissociation and the rates of reaction are similar, see: Landis, C. R.;

Halpern, J. J. Am. Chem. Soc. 1987, 109, 1746–1754.

(54) Bachrach, S. M. Computational Organic Chemistry; Wiley: Hoboken,

NJ, 2007.

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15364 J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009

Amido-Thiourea Catalyzed Imine Hydrocyanation

A R T I C L E S

Scheme 6. Amido-(thio)urea Controlled HNC Addition to Imine^a

^aBond distances (Å) for X ) S are shown. All energies are relative to the energy calculated for 10a or the analogous urea-derived complex.

talysis.⁵⁵We thus turned to computational methods to obtain

deeper insight into the reaction mechanism and to identify

catalyst-substrate interactions responsible for catalysis and

asymmetric induction.⁵⁶Catalyst 8a and model substrate 9a have

limited conformational ﬂexibility, were therefore selected as

starting points for comparing energies of a variety of transition

structures. Initial calculations were executed at the B3LYP/6-

31G(d) level, and all energies refer to uncorrected electronic

energies at this level of theory, unless noted otherwise. To test

the validity of using this computational method, key transition

structures were recalculated at the MP2/6-31G(d) and M05-2X/

6-31+G(d,p) levels.⁵⁷

effect of amide structure on reaction rate and enantioselectivity.

The computational analysis reveals that proton transfer from

one of the N-protons of the thiourea occurs to the imine nitrogen

simultaneously with cyanide addition.⁵⁸This proton transfer

would be expected to lead to positive charge development on

the imine in the rate-limiting transition structure and therefore

appears to be consistent with the results of the Hammett analysis

(Figure 4).

However, both rate data comparing the urea and thiourea

catalysts and isotopic labeling data allow us to rule out the

mechanism in Scheme 6. Thioureas are more acidic than ureas

by approximately 6 pK_aunits, and this difference in acidity

holds across a broad range of substitution patterns.⁵⁹If the

thiourea or urea catalyst undergoes deprotonation prior to or

during the rate-limiting step, then thiourea 4a is expected to

be substantially more active than urea 4b. Indeed, the

computational analysis of the thiourea-bound-to-imine mech-

anism (Scheme 6) predicts that the activation energy for the

urea-catalyzed reaction is 5.3 kcal/mol greater than for the

thiourea-catalyzed reaction.⁶⁰However, this effect is not

borne out experimentally: 4a catalyzes imine hydrocyanation

of a range of substrates only slightly more rapidly than 4b

(2-3-fold, see Figure 4 and Table 2).

To establish a reference point for analysis of transition

structures, ternary complexes of imine, HCN, and catalyst were

identiﬁed. Complexes 10a-c involving either thiourea-cyanide

or thiourea-imine interactions are each stabilized by three

hydrogen bonds and were found to be nearly isoenergetic.

In the thiourea-bound-to-imine mechanism (Scheme 6), a

thioureaprotonisincorporatedintotheR-aminonitrileproduct.^25c-e

Identiﬁcation the origin of the N-proton in the R-aminonitrile

product would therefore provide a straightforward test of the

plausibility of this mechanistic proposal. Amido-urea deriva-

tive 7b was identiﬁed as an efﬁcient and enantioselective imine

hydrocyanation catalyst in which the urea N-H resonances could

1

be monitored by H NMR spectroscopy under the catalytic

reaction conditions. When deuterium cyanide rather than

hydrogen cyanide is used as a cyanide source, exchange of the

N-protons of 7b occurs slowly, both in the absence and presence

of imine. Hydrocyanation of imine 2c proceeds more rapidly

than hydrogen/deuterium exchange, and nearly quantitative

deuterium incorporation into the R-aminonitrile product is

1. Addition of Hydrogen Cyanide to Thiourea-Bound Imine.

One possible mechanism for imine hydrocyanation involves

direct imine activation by catalyst via an imine-thiourea

complex.¹¹Within such a mechanism, a possible role of the

amide might be to activate HCN or HNC to generate a more

active nucleophile.^25bTransition state calculations indicate that

a mechanism involving a combination of amide-HNC and

thiourea-imine interactions has a high activation barrier but is

viable (Scheme 6). Because this mechanistic proposal suggests

a direct role for the amide, it might also help explain the strong

1

observed by H NMR spectroscopy well before one catalytic

turnover is reached (eq 3 and Figure. 6). Under these conditions,

only small amounts of exchange between the urea N-protons

and DCN are observed (compare the integration of the N-protons

(58) An analogous mechanism that involves proton transfer from the other

thiourea N-proton has also been characterized by computational

methods, and has a slightly higher activation energy.

(59) (a) Bordwell, F. G.; Algrim, D. J.; Harrelson, J. A., Jr. J. Am. Chem.

Soc. 1988, 110, 5903–5904. (b) Bordwell, F. G.; Ji, G.-Z. J. Am.

Chem. Soc. 1991, 113, 8398–8401.

(55) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk,

K. N. Acc. Chem. Res. 2004, 37, 558–569.

(60) Expected relative rates of catalysis can be estimated from this energy

q

difference: rate_thiourea/rate_urea≈ e^{(-∆∆E /RT)}) 20 000 at 0 °C.

(61) Reactions run to greater than one catalytic turnover show substantial

amounts of proton exchange both in the presence and absence of

substrate, and consequently display signiﬁcant proton-incorporation

into the R-aminonitrile product. Details are provided in the Supporting

Information.

(56) Calculations were executed within Frisch, M. J.; , et al. Gaussian

03, ReVision E.01; Gaussian, Inc.: Wallingford, CT, 2004.

(57) For a comparison of these computational methods in the context of

asymmetric catalysis, see: Li, X.; Liu, P.; Houk, K. N.; Birman, V. B.

J. Am. Chem. Soc. 2008, 130, 13836–13837.

9

J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009 15365

A R T I C L E S

Zuend and Jacobsen

the possibility that chiral amido-thiourea catalysts might promote

hydrocyanation via an analogous mechanism. The computational

analysis depicted in Scheme 7 indicates that HCN-mediated

imine hydrocyanation can proceed by thiourea-assisted proton

transfer from HCN to imine to form a transient catalyst-bound

ion pair that collapses to form the R-aminonitrile product (A

f C). The iminium ion in the transition structure (B) is

stabilized by a tight H-bond to the amide moiety of the catalyst,

whereas the cyanide anion is stabilized by a dual H-bond to

the thiourea moiety of the catalyst. The computational analysis

with this simpliﬁed catalyst suggests that this process is formally

concerted but highly asynchronous: the C-H bond between

cyanide and iminium ion is partially broken in the transition

structure, but almost no C-C bond formation has occurred at

this point on the reaction coordinate. The reaction coordinate

with this simpliﬁed model involves rate-limiting proton transfer

followed by barrierless cyanide addition.

An analogous mechanism that uses hydrogen isocyanide

(HNC) as the active nucleophile was also identiﬁed by

computational methods (Scheme 8).⁶³This mechanism for imine

hydrocyanation involves two discrete steps. The ﬁrst step (A

f C) involves proton transfer from HNC to imine to generate

a catalyst-bound iminium/cyanide ion pair (C). For the cyanide

anion to be able to approach the iminium ion in a Bu¨rgi-Dunitz

trajectory,⁶⁴further charge and spatial separation is necessary.

The rate-limiting step in the overall transformation involves

structural reorganization of this ion pair to form a transition

structure with a long forming C-C bond that collapses to the

R-aminonitrile (C f E). The overall activation barrier for HNC

addition is slightly lower than for HCN addition. However the

key stabilizing substrate-catalyst interactions in the transition

structures (Schemes 7B and 8D) are nearly identical: both

transition structures involve a network of medium-length

H-bonds between cyanide and thiourea (1.9-2.2 Å), between

iminium and cyanide (2.1-2.2 Å), and between amide and

iminium ion (2.2 Å).⁶⁵Because of the overall similarities

between these mechanistic hypotheses, and the limited relevance

of the simpliﬁed model system used in this study, we have not

made further efforts to distinguish between these pathways.⁶⁶

1

Figure 6. Partial H NMR spectra of reactions depicted in eq 3 after 25

min using (A) DCN, catalyst 6b, and imine 2h, (B) HCN, catalyst 6b, and

imine 2h, or (C) DCN and catalyst 6b. Data were collected at 32 °C. Under

these conditions, the catalyst exists as a 5:1 mixture of amide rotamers.

Deuterium incorporation at the N-H position of the R-aminonitrile can be

assessed by analyzing the coupling pattern of the C(CN)H proton (δ 4.3

ppm). The experiment containing DCN displays quantitative deuterium

incorporation into the R-aminonitrile, whereas the experiment containing

HCN displays quantitative proton incorporation into the R-aminonitrile. HCN

and DCN were generated from TMSCN and MeOH or MeOD. The

enantiomeric excess of the R-aminonitrile isolated from these reactions is

84-85%.

in Figure 6A, B, and C).⁶¹These observations lead to the

conclusion that the source of the N-proton on the R-aminonitrile

is HCN rather than catalyst, and this is inconsistent with the

mechanism depicted in Scheme 6. It is thus necessary to consider

alternative mechanistic possibilities for imine hydrocyanation.⁶²

The mechanistic hypothesis that either HCN or HNC proto-

nates the imine to generate a catalyst-bound ion pair (Schemes

7 and 8) is consistent with the experimental data: (a) each of

the proposed mechanisms involves positive-charge buildup on

the imine, and is thus consistent with the Hammett analysis;

(b) each proposed mechanism involves imine protonation by

the nucleophile rather than the catalyst, and is thus consistent

with the experimental observation that R-aminonitrile N-proton

originates from the nucleophile rather than from the catalyst.

In addition, the overall calculated activation barrier for hydro-

2. Addition of Cyanide to Catalyst-Bound Iminium Ion. As

discussed above, the proposed mechanism for water-mediated

imine hydrocyanation involves proton transfer from HCN to

imine to form an iminium/cyanide ion pair, followed by collapse

to form the R-aminonitrile product (Figure 2A).²²We considered

(63) One possible mechanism for HCN-HNC isomerization is via a cyclic

trimer or higher oligomer: Sa´nchez, M.; Provasi, P. F.; Aucar, G. A.;

Alkorta, I.; Elguero, J. J. Phys. Chem. B. 2005, 109, 18189–18194.

HCN-HNC isomerization in the presence of imine and catalyst is

also possible, and the process may in principle occur on the catalytic

cycle (see the Supporting Information).

(62) It is possible, in principle, that the simpliﬁed computational model

over-estimates the acidity of the thiourea protons or the basicity of

the partially-formed R-aminonitrile anion, and that no proton transfer

between thiourea and imine occurs. Within this alternative mecha-

nism, the partially formed R-aminonitrile anion would be stabilized

by H-bonding in an interaction reminiscent of those interactions

present in an enzymatic oxyanion hole (see: ref 16c, and refs therein).

This mechanistic proposal is depicted in Scheme 4A, and is

inconsistent with the Hammett analysis (Figure 4).

(64) Bu¨rgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973, 95,

5065–5067.

(65) For a discussion of H-bonding, see: Jeffrey, G. A. An Introduction

to Hydrogen Bonding; Oxford University Press: New York, 1997.

(66) For a detailed analysis of the relative reactivity of HCN and HNC in

catalyst-controlled cyanide addition to aldehydes, and leading refer-

ences, see: Baeza, A.; Na´jera, C.; Sansano, J. M.; Saa´, J. M.

Chem.sEur. J. 2005, 11, 3849–3862.

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Amido-Thiourea Catalyzed Imine Hydrocyanation

A R T I C L E S

Scheme 7. Catalyst-Controlled, HCN-Mediated Imine Hydrocyanation

Scheme 8. Catalyst-Controlled, HNC-Mediated Imine Hydrocyanation

cyanation via an iminium/cyanide ion pair is 20 kcal/mol lower

than hydrocyanation by direct addition to a catalyst-bound

imine.⁶⁷

The similarities in the transition structure geometries thus

provide an explanation for why transition structures formally

originating from tautomeric nucleophiles have such similar

energies. Nevertheless, the HNC-addition are more favorable

than HCN-addition transition structures in every case examined,

and our analysis is therefore focused on HNC-addition mode

for the remainder of this paper.⁶⁸

Calculations of the HNC-addition transition structuress

including full geometry optimizationssat the M05-2X/6-

31+G(d,p) and MP2/6-31G(d) levels yield nearly identical

transition structures and relative energies (Supporting Informa-

tion). This mechanistic proposal is thus consistent with the

The HCN- and HNC-addition transition structures leading

to the (R)- and (S)-enantiomers of R-aminonitrile are depicted

in Figures 7 and 8. Each of the two sets of structures differs

with respect to the orientation of the substrate tert-butyl group

relative to the catalyst, but both possess the same cyanide-

thiourea and iminium-amide interactions. The HCN- and HNC-

addition transition structures leading to each enantiomer of

product are remarkably similar, and differ only in the orientation

of the cyanide anion relative to the catalyst and iminium ion.

(67) The calculated activation barrier for the analogous process catalyzed

by urea 8b is 1.4 kcal/mol higher than the process catalyzed by

thiourea 8a.

(68) The conclusions described in this paper for HNC addition also apply

to HCN-addition. All data for the HCN addition mode are included

in the Supporting Information.

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A R T I C L E S

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to evaluate catalyst and substrate structures that are more

relevant to the catalytic, enantioselective reaction.

E. Computational Analysis of Imine Hydrocyanation with

Substituted Amido-Thiourea Catalysts. A broad range of enan-

tioselectivities are observed in imine hydrocyanation with

different amido-(thio)urea catalysts (Table 2), and we sought

to determine whether computational methods can be used to

account for the observed trends in a quantitative manner.^70,71

For such an analysis to be meaningful, the computational models

must incorporate all the catalyst and substrate structural features

necessary for high enantioselectivity. As discussed above, both

the identity of the amide and the amino acid components play

crucial roles in deﬁning the enantioselectivity of the catalyst.

In contrast, the precise structure of the anilino group has little

effect on enantioselectivity (Table 2, entries 1-3), so we

selected the simple phenyl-substituted catalyst 6a, together with

an imine that undergoes hydrocyanation with high ee, N-

benzhydryl imine 2a, for our model. In the following discussion,

energies of all calculated intermediates and transition structures

are provided relative to the stable complex between catalyst,

substrate, and HCN shown below.

Figure 7. Calculated transition structures for HCN addition to imine 9a

catalyzed by 8a (B3LYP/6-31G(d)). Transition structures leading to (A)

(R)-R-aminonitrile and (B) (S)-R-aminonitrile are shown.

Scheme 9 provides a representation of the calculated inter-

mediates and transition states in the lowest energy pathway for

the addition of HNC to imine 2a catalyzed by thiourea 6a. The

ﬁrst two steps of this mechanism (A f C f E) involve

formation of a catalyst-bound iminium-cyanide ion pair. This

ion pair then undergoes structural rearrangement to form new

ion pair in which the iminium ion is associated to the amide

component of the catalyst (E f G). In this model system, there

is a small barrier calculated for the collapse of this ion pair to

form the (R)-R-aminonitrile product (G f I). As with the

simpler model system described above, the highest energy

transition state, and therefore the rate-limiting step, is associated

with the ion pair reorganization step (compare Scheme 8C f

E with Scheme 9E f G). In short, the basic calculated HNC-

mediated imine hydrocyanation mechanisms are predicted to

correspond closely in the small and large model systems; the

mechanisms differ only in the number of intermediates and

transition structures that are observed prior to and after the rate-

limiting step.

Figure 8. Calculated transition structures for HNC addition to imine 9a

catalyzed by 8a (B3LYP/6-31G(d)). Transition structures leading to (A)

(R)-R-aminonitrile and (B) (S)-R-aminonitrile are shown.

An analogous computational analysis of the formation of the

(S)-R-aminonitrile yields a similar reaction coordinate (Sup-

porting Information), in which a transition structure akin to F

experimental data, and the geometries of the transition structures

are consistent across different theoretical methods; we thus

conclude that an imine hydrocyanation mechanism involving a

catalyst-bound iminium/cyanide ion pair is viable. However the

simpliﬁed model system examined in this study does not serve

to address the high enantioselectivity observed experimentally

in the catalytic reaction.⁶⁹To account for the experimental

catalyst structure-activity data (Table 2) and attempt to develop

an understanding of the basis of stereoinduction, it is necessary

(69) This simpliﬁed model system predicts a small preference for formation

of (S)-R-aminonitrile, whereas (R)-R-aminonitrile is obtained from

hydrocyanation reactions using the full catalyst. For consistency, all

schemes in this chapter depict formation of (R)-R-aminonitrile. The

corresponding schemes for formation of (S)-R-aminonitrile are

included in the Supporting Information.

(70) Donoghue, P. J.; Helquist, P.; Norrby, P.-O.; Wiest, O. J. Am. Chem.

Soc. 2009, 131, 410–411.

(71) Schneebeli, S. T.; Hall, M. L.; Breslow, R.; Friesner, R. J. Am. Chem.

Soc. 2009, 131, 3965–3973.

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15368 J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009

Amido-Thiourea Catalyzed Imine Hydrocyanation

A R T I C L E S

Scheme 9. Catalyst-Controlled, HNC-Mediated Imine Hydrocyanation

is predicted to represent the rate-limiting step (E ) +19.4 kcal/

mol). The calculated relative energies of the ion pair rearrange-

ment transition structures (∆∆E^q) 2.4 kcal/mol) thus corre-

spond well with the experimentally observed preference for

formation of the (R)-R-aminonitrile. This analysis assumes that

the calculated rate-limiting step, E f G, is enantioselectivity-

determining. It is important to note that the calculations also

predict the same sense and similar magnitude of enantioselec-

tivity if the cyanide-addition step, G f I, is enantioselectivity-

determining. Thus comparison of the energies of transition

structure H (Scheme 9) and the corresponding structure leading

to the (S)-R-aminonitrile (Supporting Information) also reveals

a signiﬁcant preference for formation of (R)-R-aminonitrile

(∆∆E^q) 2.1 kcal/mol). The computational analysis therefore

provides support for either iminium-ion rearrangement or

cyanide addition as enantioselectivity-determining steps in the

catalytic reaction, although it predicts a higher barrier to the

former.

H in Scheme 9 is rate-determining might be addressed by

examining secondary isotope effects in the hydrocyanation

reaction. A key difference between these transition structures

is that H undergoes partial sp²f sp³rehybridization of the

electrophilic carbon atom, whereas F does not. Secondary

R-hydrogen/deuterium kinetic isotope effects (KIEs, k_H/k_D) are

sensitive probes of changes in carbon hybridization state,⁷²and

inverse R-KIEs are observed in reactions thought to involve

signiﬁcant sp²f sp³rehybridization (typically, k_H/k_D

0.75-0.90).⁷³

≈

However, in reactions of carbonyl derivatives that involve

reversible protonation or Lewis acid complexation of the

carbonyl prior to nucleophilic addition, it is also necessary to

consider secondary ꢀ-hydrogen/deuterium equilibrium isotope

effects (EIEs) on lone pair basicity.⁷⁴Accurate and systematic

(72) Streitwieser, A., Jr.; Jagow, R. H.; Fahey, R. C.; Suzuki, S. J. Am.

Chem. Soc. 1958, 80, 2326–2332.

(73) For example, in cyanide addition to aldehydes: Okano, V.; do Amarol,

L.; Cordes, E. H. J. Am. Chem. Soc. 1976, 98, 4201–4203.

(74) (a) Gajewksi, J. J.; Ngernmeesri, P. Org. Lett. 2000, 2, 2813–2815.

(b) Gajewski, J. J.; Bocian, W.; Brichford, N. L.; Henderson, J. L. J.

Org. Chem. 2002, 67, 4236–4240.

F. Secondary Kinetic Isotope Effect Experiments. We ex-

plored alternative approaches to establish the identity of the

enantioselectivity-determining step with greater certainty. In

principle, the question of which of transition structures F and

9

J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009 15369

A R T I C L E S

Zuend and Jacobsen

measurements of ꢀ-EIEs on nitrogen basicity have been reported

only recently, and these studies have revealed that ꢀ-deuterium

substituted amines are more basic than their ꢀ-protio analogues

in aqueous solution.⁷⁵By extrapolation of the experimental data,

a maximum ꢀ-EIE on basicity of ∼46 cal/mol is predicted when

the C-H or C-D bond is antiperiplanar to the basic nitrogen

(k_H/k_D) 0.93 at 298 K).⁷⁶This effect is reproduced using

harmonic frequency calculations at the MP2/6-31G(d,p) level

(k_H/k_D) 0.91).⁷⁷C-H stretching frequencies involving sp²-

hybridized carbons are affected by the presence of an anti-

periplanar lone pair;^74,78because secondary isotope effects can

arise any time a vibrational mode is perturbed in the course of

a reaction, an EIE might be expected in imine protonation as

well.

Figure 9. Amido-thioureas used in quantitative computational analysis.

in our analysis with the assumption that the iminium ion

rearrangement (E f G) is enantioselectivity-determining.

To test this notion, we calculated the EIE for protonation of

a model imine at the MP2/6-31G(d,p) level using harmonic

frequency calculations (eq 4).^79,80This analysis predicts a

signiﬁcant inverse EIE on imine basicity comparable in mag-

nitude to the inverse EIE observed experimentally on tertiary

amine basicity. Thus the direction of the secondary ꢀ-EIE on

imine basicity is expected to be the same as the direction of

the secondary R-KIE in a reaction involving sp²f sp³

rehybridization in the transition state. In the asymmetric imine

hydrocyanation, an inverse KIE of k_H/k_D) 0.88 ( 0.03 is

observed (eq 5).⁸¹An isotope effect of this magnitude allows

us to rule out a late transition state involving a largely sp³-

hybridized electrophilic carbon,⁷³but it is consistent with a

transition state that involves either early C-C bond formation

or iminium ion rearrangement.⁸²Therefore, the experimental

secondary isotope effect data are consistent with either F or H

(Scheme 9) as the rate- and enantioselectivity-determining

transition structures. Given that the calculations predict a very

low barrier for the cyanide addition step (G f I), we proceeded

G. Correlation between Experimental and Calculated

Enantioselectivity. The experimental enantioselectivity data

listed in Table 2 reveal a strong impact of relatively small

changes in catalyst structure on enantioselectivity in the

hydrocyanation of 2a.⁸³Diastereomeric transition structures akin

to F depicted in Scheme 9 for addition of HNC to imine 2a

were calculated at the B3LYP/6-31G(d) level for a series of

catalysts. Experimental data listed in Table 2 from reactions

run with catalysts 4a-4h were compared with calculations

executed using the N-phenyl catalysts 6a-6h (Figure 9). A plot

of the relative energies of the (S)- and (R)-transition structures

versus the energy difference between (S)- and (R)-transition

states calculated from experimental ee measurements yields a

strong correlation and a statistically signiﬁcant positive slope

(Figure 10).⁸⁴Single-point energy calculations at the M05-2X/

6-31+G(d,p) and MP2/6-31G(d) levels result in similar plots

(Figures 11 and 12).^85,86Computations at each level of theory

reproduce the experimentally observed preference for the (R)-

enantiomer of product, the higher observed enantioselectivity

with 4d compared with 4e, the reduced enantioselectivity with

secondary amide catalyst 4g compared with tertiary amide

catalyst 4a, and the preference for the (S)-enantiomer of product

with catalyst 4f.⁸⁷

(75) (a) Perrin, C. L.; Ohta, B. K.; Kuperman, J. J. Am. Chem. Soc. 2003,

125, 15008–15009. (b) Perrin, C. L.; Ohta, B. K.; Kuperman, J.;

Liberman, J.; Erde´lyi, M. J. Am. Chem. Soc. 2005, 127, 9641–9647.

(c) Perrin, C. L.; Dong, Y. J. Am. Chem. Soc. 2008, 130, 11143–

11148.

(76) The origins of this effect have been ascribed to a modulation of the

C-H stretching frequency. See ref 75b for the determination of this

EIE and a discussion of its origins. In that paper, EIEs are expressed

in terms of the acidity of the conjugate acid of the amines.

(77) Determined at 298.15 K. Explicit solvation by water likely accounts

for some of the discrepancy between experiment and computation,

as larger ꢀ-EIEs were observed in a more limited experimental study

in DMSO.

(78) Bellamy, L. J.; Mayo, D. W. J. Phys. Chem. 1976, 80, 1217–1220.

(79) We used this computational method to allow direct comparison with

the results in ref 74b.

(80) This isotope effect was calculated from the calculated 3N-6 normal

mode vibrational frequencies using the isotopic partition function of

Biegeleisen and Mayer at T ) 298.15 K. In each case, sufﬁciently

tight geometry optimization convergence criteria were used so that

all non-vibrational frequencies (i.e., the six rotational and translational

frequencies) were negligible (-1 to 1 cm^-1) compared with the

vibrational frequencies (> 100 cm^-1). See:Wolfsberg, M. Comments

on Selected Topics in Isotope Theoretical Chemistry. In Isotope

Effects in Chemistry and Biology; Kohen, A.; Limbach, H.-H., Eds.;

CRC Press: Boca Raton, FL, 2006; Chapter 3.

(83) Several lines of evidence suggest that the pathways leading to (R)-

and (S)-3a are mechanistically consistent for the different catalysts.

For example, the same trends in enantioselectivity are observed for

both aromatic and aliphatic imines, and under a broad range of

different conditions, including different temperatures, cyanide sources,

and concentrations. Data are included in the Supporting Informa-

tion.

(81) This kinetic isotope effect was determined by ¹H-NMR spectroscopy

through competition experiments of reactions run to approximately

70% conversion, in which the hydrogen/deuterium ratios were

determined in both product and recovered starting material. Details

are provided in the Supporting Information.

(84) Statistical analysis was performed using SigmaPlot 10.0 purchased

from Systat Software.

(85) Alanine-derived catalyst 4h represents the large positive outlier in

Figures 11 and 12. This catalyst is also substantially less reactive

than any other catalyst, perhaps as a result of catalyst aggregation.

It is likely that the experimentally measured enantioselectivity reﬂects

a signiﬁcant background racemic pathway and therefore underesti-

mates the intrinsic enantioselectivity for this catalyst.

(82) We have also calculated analogous kinetic isotope effects for transition

structure D in Scheme 8 relative to free imine at the B3LYP/6-31G(d)

level using 3N^q-7 vibrational modes for D. The predicted k_H/k_D

)

0.86 at 298 K or k_H/k_D) 0.82 at 243 K is similar to the

experimentally observed KIE (eq 5).

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15370 J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009

Amido-Thiourea Catalyzed Imine Hydrocyanation

A R T I C L E S

Figure 10. Calculated versus experimental enantioselectivity of HNC

addition to 2a at the B3LYP/6-31G(d) level. Plot of calculated ∆∆E^qof

HNC-addition transition structures versus estimated experimental ∆∆G^q

(Table 2, entries 1, 4-10). The curve represents a least-squares ﬁt to f(x)

) a + bx, a ) 0.1 ( 0.2 kcal/mol, b ) 1.2 ( 0.2, R²) 0.87, P_b) 0.0006.

Figure 11. Calculated versus experimental enantioselectivity of HNC

addition to 2a at the M05-2X/6-31+G(d,p)//B3LYP/6-31G(d) level. Plot

of calculated ∆∆E^qof HNC-addition transition structures versus estimated

experimental ∆∆G^q(Table 2, entries 1, 4-10). The curve represents a least-

squares ﬁt to f(x) ) a + bx, a ) -0.5 ( 0.4 kcal/mol, b ) 1.9 ( 0.4, R²

) 0.79, P_b) 0.0033.

H. Basis for Enantioselectivity: The Role of Cation Stabiliza-

tion. The computational data are strongly consistent with the

experimental observation that the enantioselectivity of imine

hydrocyanation is strongly dependent on the structure of the

catalyst. However, comparison of imine hydrocyanation transi-

tion structures using catalysts that induce high enantioselectivity

in hydrocyanation (e.g., catalyst 6a, Figure 13) with those that

induce low enantioselectivity (e.g., catalyst 6f, Figure 14) reveals

few obvious differences. In particular, there are no apparent

“steric clashes” that might explain why some transition structures

are signiﬁcantly higher in energy than the one leading to (R)-

3a with catalyst 6a. We therefore undertook a quantitative

analysis of structural differences between transition structures

using different catalysts. As described below, this analysis has

led to the conclusion that enantioselectivity can be attributed

primarily to differential stabilization of the iminium cation.

Because imine hydrocyanation is catalyzed by simple H-bond

donors (i.e., Schreiner’s catalyst, 5), we considered whether the

basis for enantioselectivity might be tied to the dual H-bond

interaction between cyanide and (thio)urea. The strength of

H-bonds is distance-dependent;⁶thus, if the cyanide-thiourea

Figure 12. Calculated versus experimental enantioselectivity of HNC

addition to 2a at the MP2/6-31G(d)//B3LYP/6-31G(d) level. Plot of

calculated ∆∆E^qof HNC-addition transition structures versus estimated

experimental ∆∆G^q(Table 2, entries 1, 4-10). The curve represents a least-

squares ﬁt to f(x) ) a + bx, a ) -1.1 ( 0.4 kcal/mol, b ) 2.6 ( 0.4, R²

) 0.91, P_b) 0.0003.

H-bond strength changes substantially among the four transition

structures, the H-bond lengths in the four transition structures

would be expected to be substantially different (d₁and d₂in

Figure 15). However, the length of the dual H-bond between

thiourea and cyanide does not differ substantially among the

(R)- and (S)-transition structures with either catalyst: the eight

cyanide nitrogen-thiourea proton distances among the four

transition structures vary from 1.97 to 2.11 Å (Figures 13 and

14). The small differences in H-bond length among the different

structures can be attributed primarily to changes in binding

symmetry rather than differences in overall binding strength:

the average of the two H-bond lengths of the four structures in

Figures 13 and 14 ranges from 2.01-2.05 Å. We reach the same

conclusion from a complete analysis of all sixteen HNC-addition

transition structures calculated with imine 2a and catalysts

6a-6g (Supporting Information). Plots of the sum of the

thiourea-cyanide bond lengths (d₁+ d₂) versus calculated

enantioselectivity reveal that there is no statistically signiﬁcant

trend in H-bond length within either the (R)- or (S)-transition

structures between highly and poorly enantioselective catalysts

(86) B3LYP has been shown to under-estimate the energy of some

attractive non-covalent interactions, whereas MP2 over-estimates the

energy of these interactions. In this reaction, enantioselectivity is

controlled only by non-covalent interactions between substrates and

catalysts, and the correlation in Figures 10-12 might be expected

to depend strongly of the level of theory used. This is not the case.

This conclusion may be ascribed to the observation that the calculated

(and experimental; see Figure 4) transition structures are highly

charged, and thus the non-covalent interactions responsible for

asymmetric induction are expected to have a large electrostatic

component. Even ab initio computational methods that do not account

for electron correlation (i.e., Hartree-Fock) can account for electro-

static contributions of otherwise complex non-covalent interactions:

Mecozzi, S.; West, A. P., Jr.; Dougherty, D. A. J. Am. Chem. Soc.

1996, 118, 2307–2308.

(87) Calculated versus experimental selectivity plots for HCN addition

are included in the Supporting Information. Statistically signiﬁcant

positive linear correlation is observed in all cases. HCN addition is

disfavored compared with HNC addition for each catalyst at each

level of theory examined (by 0.2-3.7 kcal/mol). The transition

structures for HNC addition and HCN addition are similar, and the

ion pairs formed from HNC addition and HCN addition are almost

identical; it is thus not possible to further distinguish between these

two mechanistic proposals, and it is possible that both play a role in

catalytic imine hydrocyanation.

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Figure 15. H-bond distances between thiourea (X ) S) or urea (X ) O)

and cyanide anion.

Figure 13. Calculated transition structures for HNC addition to imine 2a

catalyzed by 6a. Transition structures leading to the (A) major and (B)

minor enantiomer are shown.

Figure 16. Correlation of transition structure bond length with enantiose-

lectivity for HNC addition to imine 2a. Plot of the sum of the cyanide-

(thio)urea H-bond lengths in B3LYP/6-31G(d) transition structures using

catalysts 6a-6h versus experimental energy difference between (R)- and

(S)-transition states estimated using catalysts 4a-4h (Table 2). The black

curves represent a least-squares ﬁt to f(x) ) a + b x; (R)-TS: a ) 4.01 (

0.02 Å, b ) 0.02 ( 0.02 Å mol kcal^-1, R²) 0.24, P_b) 0.22; (S)-TS: a )

4.11 ( 0.01 Å, b ) -0.02 ( 0.01 Å mol kcal^-1, R²) 0.34, P_b) 0.13.

Figure 17. Qualitative reaction coordinate diagram for iminium/cyanide

ion pair rearrangement depicting H-bond distances between iminium ion,

cyanide anion, and catalyst amide.

Figure 14. Calculated transition structures for HNC addition to imine 2a

catalyzed by 6f. Transition structures leading to the (A) minor and (B) major

enantiomer are shown.

transition structure represents a point on the reaction coordinate

where the H-bonds from iminium ion to both cyanide (d₃) and

amide (d₄) are each partially formed (Figure 17).⁸⁸A straight-

forward way to estimate the overall H-bond strength to the

iminium ion as the rearrangement proceeds is to measure the

sum of the O-H and N-H bond lengths in the HNC-addition

transition structures (d₃+ d₄).⁸⁹Plots of the sum of the H-bond

lengths versus calculated enantioselectivity reveal that d₃+ d₄

(Figure 16). Thus, there is no correlation between thiourea-

cyanide H-bond length and enantioselectivity, and other expla-

nations must be evaluated for the basis for enantioselectivity.

The calculated rate-limiting step (E f G, Scheme 9) is

rearrangement of an ion pair: in intermediate E, the iminium

ion forms an H-bond to cyanide anion; in intermediate G, the

iminium ion forms an H-bond to the oxygen atom of the catalyst

carbonyl group. The reaction coordinate thus formally involves

transfer of the iminium ion from cyanide to carbonyl, and the

(88) The length of the N-H bond between imine and proton is 1.03-1.04

Å in the transition structure, and is thus effectively fully formed (i.e.,

the transition structure has nearly complete iminium ion character).

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Amido-Thiourea Catalyzed Imine Hydrocyanation

A R T I C L E S

Small-molecule organocatalysts promote asymmetric trans-

formations via a variety of fundamentally different activation

mechanismssincluding covalent catalysis,⁴general acid-base

catalysis,¹⁶and noncovalent catalysis^91-93sand these activation

modes closely parallel those of enzymatic reactions.⁹⁴However,

small-molecule organocatalysts appear to differ from their

macromolecular counterparts in their propensity to bind sub-

strates. The measurement of substrate binding constants is a

hallmark of enzymatic kinetic analyses,⁹⁵and it is a guiding

principle in structural biology that the binding orientation of

the substrate in an enzyme active site at least partially relevant

to the transition structure.⁹⁶In contrast, kinetically observable

substrate binding does not occur in the reaction studied herein,

and computational studies suggest that multiple, fundamentally

different binding modes are in principle isoenergetic (i.e.,

complexes 10a-10c). Imine-urea binding was observed both

kinetically and spectroscopically in the context of imine

hydrocyanation catalyzed by 1b (Figure 1),¹¹but the results

described in this paper suggest that this mode of imine binding

lies off the productive catalytic cycle.^97-99

Figure 18. Correlation of transition structure bond length with enantiose-

lectivity for HNC addition to imine 2a. Plot of the sum of the cyanide

N-iminium H + amide O-iminium H bond lengths in B3LYP/6-31G(d)

transition structures using catalysts 6a-6h versus experimental energy

difference between (R)- and (S)-transition structures using catalysts 4a-4h

(Table 2). The black curves represent a least-squares ﬁt to f(x) ) a + bx;

(R)-TS: a ) 4.527 ( 0.01 Å, b ) 0.039 ( 0.009 Å mol kcal^-1, R²) 0.75,

This difference in the relevance of the ground state catalyst-

substrate structure to the mechanism of catalysis may be ascribed

simply to the structural simplicity of these small-molecule

P_b) 0.0054; (S)-TS: a ) 4.59 ( 0.04 Å, b ) 0.25 ( 0.04 Å mol kcal^-1

R²) 0.88, P_b) 0.0005.

,

varies only slightly across the transition structures leading to

the (R)-enantiomer (Figure 18). In contrast, there is a positive

correlation between d₃+ d₄and enantioselectivity within the

(S)-transition structures. Comparison of the most and least

selective catalysts is striking: whereas d₃+ d₄is signiﬁcantly

different between the (R)- and (S) addition transition structures

with optimal catalyst 6a (4.58 versus 5.00 Å, Figure 13), this

difference is negligible with catalyst 6f (4.51 Å for both (R)-

and (S)-transition structures, Figure 14). This analysis leads to

a simple conclusion: the basis for enantioselectivity may be

traced to different degrees of iminium ion stabilization among

different catalysts and diastereomeric transition structures, and

stabilization of the iminium ion is achieved by H-bonding

interactions between the iminium ion N-H and both the amide

CdO and the thiourea-bound cyanide ion.

(90) See, for example: (a) Reference 44. (b) Mita, T.; Jacobsen, E. N.

Synlett 2009, 1680–1684.

(91) For examples of cationic chiral catalysts thought to operate through

non-covalent interactions see: (a) Hashimoto, T.; Maruoka, K. Chem.

ReV. 2007, 107, 5656–5682. (b) Uyeda, C.; Jacobsen, E. N. J. Am.

Chem. Soc. 2008, 130, 9228–9229. For computational analysis of

reactions catalyzed by chiral, quaternary ammonium salts (i.e., phase-

transfer catalysis), see: (c) Cannizarro, C. E.; Houk, K. N. J. Am.

Chem. Soc. 2002, 124, 7163–7169. (d) Gomez-Bengoa, E.; Linden,

A.; Lo´pez, R.; Mu´gica-Mendiola, I.; Oiarbide, M.; Palomo, C. J. Am.

Chem. Soc. 2008, 130, 7955–7966. See also: (e) Corey, E. J.; Xu,

F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414–12415.

(92) For examples of anionic chiral catalysts thought to operate through

non-covalent interactions, see: (a) Mayer, S.; List, B. Angew. Chem.,

Int. Ed. 2006, 45, 4193–4195. (b) Hamilton, G. L.; Kanai, T.; Toste,

F. D. J. Am. Chem. Soc. 2008, 130, 14984–14986. For a review on

chiral anions, see: (c) Lacour, J.; Hebbe-Viton, V. Chem. Soc. ReV.

2003, 32, 373–382.

(93) For other examples of neutral chiral catalysts thought to operate

through non-covalent interactions, see: ref 1.

(94) See, for example: (a) Jencks, W. P. Catalysis in Chemistry and

Enzymology; Dover Publications: New York, 1987; Chapter 2

(covalent catalysis), Chapter 3 (general acid-base catalysis), and

Chapters 6 and 7 (hydrogen bonding and electrostatic forces in

catalysis). (b) Silverman, R. B. The Organic Chemistry of Enzyme-

Catalyzed Reactions; Academic Press: San Diego, 2002; pp 18-20

(covalent catalysis), pp 20-28 (general acid-base catalysis), pp 28-

30 (electrostatic catalysis).

(95) Segel, I. H. Enzyme Kinetics; John Wiley & Sons: New York, 1975.

(96) See, for example, the discussions in: (a) Lipscomb, W. N. Acc. Chem.

Res. 1982, 15, 232–238. (b) Benkovic, S. J.; Hammes-Schiffer, S.

Science 2003, 301, 1196–1202.

Conclusions

This study provides experimental and theoretical support for

a mechanism for amido-thiourea catalyzed imine hydrocyanation

involving formation of an iminium/cyanide ion pair that is bound

to catalyst through multiple noncovalent interactions. This

mechanism is analogous to the mechanism proposed for

nonasymmetric imine hydrocyanation in polar, protic solvents,

in which hydrogen cyanide activates the imine toward nucleo-

philic attack. In contrast, the data are inconsistent with mech-

anisms that involve direct imine activation by thiourea. The

proposal that a H-bond donor catalyst promotes nucleophilic

addition to a basic substrate without a direct interaction between

the catalyst’s acidic and substrate’s basic functional groups may

be relevant to catalytic asymmetric nucleophilic additions of

other protic nucleophiles.⁹⁰While stabilization of the cyanide

anion by the thiourea is important for catalysis, differences in

enantioselectivity cannot be traced to the degree of anion-

stabilization. Instead, we conclude that the degree of stabilization

of the iminium ion is principally responsible for controlling

enantioselectivity in asymmetric imine hydrocyanation.

(97) The imine binding constant in the kinetic analysis of reactions

catalyzed 1b is small (K_M) 0.214 ( 0.009 M). Under the conditions

of our kinetic analysis with catalyst 4a, we estimate that K_Mvalues

less than 0.5 would be detectable. The differences in binding constant

observed in the two analyses may be ascribed to differences in

reaction temperature (-78 °C versus 0 °C) and/or to the imine

N-protecting group (allyl versus benzhydryl).

(98) Even in cases in which electrophile-thiourea interactions are produc-

tive, the binding geometry in the ground state can differ substantially

from that in the transition state. For example, ketone-thiourea binding

can occur through one or both lone pairs of the carbonyl group, and

the calculated energies of these binding modes are nearly identical

(Fuerst, D. E. Unpublished results from this laboratory). In the

nucleophilic addition transition structure, the partially formed alkoxide

binds in a way that resembles neither of the low-energy ground state

structures (ref 16c).

(89) This analysis ignores any role of bond angle in determining bond

energy, and ignores the possibility that bond strength does not

necessarily depend linearly on bond length.

(99) For a related analysis comparing binding geometries of carbonyl

compounds to chiral diols in the ground state and transition state,

see: Go´mez-Bengoa, E. Eur. J. Org. Chem. 2009, 1207–1213.

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catalysts compared with enzymes. There is no well-deﬁned and

structurally rigid “binding pocket” in catalysts such as 4a;

instead, the functional groups necessary for catalysis are exposed

to solvent and accessible to a broad range of small molecules,

whether or not they are substrates for catalysis. Indeed, the

ability of these catalysts to accept many different small-

molecules is a prerequisite both for broad substrate scope within

any single reaction and for the ability of a single catalyst to

promote multiple different reactions. A corollary of this analysis

is that enantioselectivity is under Curtin-Hammett control and

elucidation of its basis therefore requires detailed understanding

of transition structure geometries. The present study demon-

strates that weak interactions operating in transition states of

polar asymmetric reactions are amenable to quantitative char-

acterization using modern but increasingly inexpensive com-

putational methods.¹⁰⁰We suggest that systematic application

of hybrid experimental-computational approaches such as those

described in this paper will prove valuable in the characterization

of other enantioselective catalytic processes that rely on non-

covalent interactions.

Acknowledgment. This work was supported by the NIH (GM-

43214) and by fellowship support to S.J.Z. from the American

Chemical Society and Roche. We thank Dr. Lars P. C. Nielsen for

helpful discussions.

Supporting Information Available: Complete experimental

procedures, characterization data, ¹H NMR spectra used in

isotopic labeling and isotope effect experiments, kinetic data

in tabular format, geometries and energies of calculated station-

ary points, computed harmonic frequencies used in isotope effect

calculations, and complete ref 56. This material is available free

of charge via the Internet at http://pubs.acs.org.

(100) For an alternative approach, see: (a) Pluth, M. D.; Bergman, R. G.;

Raymond, K. N. Science 2007, 316, 85–88. (b) Pluth, M. D.;

Bergman, R. G.; Raymond, K. N. J. Org. Chem. 2009, 74, 58–63,

and refs therein.

JA9058958

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15374 J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009

Article Doi

Mechanism of amido-thiourea catalyzed enantioselective imine hydrocyanation: Transition state stabilization via multiple non-covalent interactions

DOI: 10.1021/ja9058958

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Article abstract of DOI:10.1021/ja9058958

Full text of DOI:10.1021/ja9058958

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